Apolipoprotein E Polymorphisms and Female Fertility in a Transgenic Mouse Model of Alzheimer's Disease

Overview

Journal Sci Rep

Specialty Science

Date 2024 Jul 9

PMID 38982272

Authors

Bani Medegan Fagla

Jason York

Amy Christensen

Cielo Dela Rosa

Deebika Balu

Christian J Pike

Leon M Tai

Irina A Buhimschi

Affiliations

Soon will be listed here.

Abstract

Apolipoprotein E (APOE) is a major cholesterol carrier responsible for lipid transport and injury repair in the brain. The human APOE gene (h-APOE) has 3 naturally occurring alleles: ε3, the common allele; ε4, which increases Alzheimer's disease (AD) risk up to 15-fold; and ε2, the rare allele which protects against AD. Although APOE4 has negative effects on neurocognition in old age, its persistence in the population suggests a survival advantage. We investigated the relationship between APOE genotypes and fertility in EFAD mice, a transgenic mouse model expressing h-APOE. We show that APOE4 transgenic mice had the highest level of reproductive performance, followed by APOE3 and APOE2. Intriguingly, APOE3 pregnancies had more fetal resorptions and reduced fetal weights relative to APOE4 pregnancies. In conclusion, APOE genotypes impact fertility and pregnancy outcomes in female mice, in concordance with findings in human populations. These mouse models may help elucidate how h-APOE4 promotes reproductive fitness at the cost of AD in later life.

References

Lumsden A, Mulugeta A, Zhou A, Hypponen E . Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank. EBioMedicine. 2020; 59:102954. PMC: 7452404. DOI: 10.1016/j.ebiom.2020.102954. View

Eisenberg D, Kuzawa C, Hayes M . Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history. Am J Phys Anthropol. 2010; 143(1):100-11. DOI: 10.1002/ajpa.21298. View

Carter A, Nguyen A . Antagonistic pleiotropy as a widespread mechanism for the maintenance of polymorphic disease alleles. BMC Med Genet. 2011; 12:160. PMC: 3254080. DOI: 10.1186/1471-2350-12-160. View

Byars S, Voskarides K . Antagonistic Pleiotropy in Human Disease. J Mol Evol. 2019; 88(1):12-25. DOI: 10.1007/s00239-019-09923-2. View

van Exel E, Koopman J, van Bodegom D, Meij J, de Knijff P, Ziem J . Effect of APOE ε4 allele on survival and fertility in an adverse environment. PLoS One. 2017; 12(7):e0179497. PMC: 5500260. DOI: 10.1371/journal.pone.0179497. View

Corbo R, Scacchi R . Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a 'thrifty' allele?. Ann Hum Genet. 2000; 63(Pt 4):301-10. DOI: 10.1046/j.1469-1809.1999.6340301.x. View

Trumble B, Charifson M, Kraft T, Garcia A, Cummings D, Hooper P . ε is associated with higher fecundity in a natural fertility population. Sci Adv. 2023; 9(32):eade9797. PMC: 10411886. DOI: 10.1126/sciadv.ade9797. View

Corbo R, Ulizzi L, Scacchi R, Martinez-Labarga C, De Stefano G . Apolipoprotein E polymorphism and fertility: a study in pre-industrial populations. Mol Hum Reprod. 2004; 10(8):617-20. DOI: 10.1093/molehr/gah082. View

Tai L, Balu D, Avila-Munoz E, Abdullah L, Thomas R, Collins N . EFAD transgenic mice as a human relevant preclinical model of Alzheimer's disease. J Lipid Res. 2017; 58(9):1733-1755. PMC: 5580905. DOI: 10.1194/jlr.R076315. View

10.

Tai L, Youmans K, Jungbauer L, Yu C, LaDu M . Introducing Human APOE into Aβ Transgenic Mouse Models. Int J Alzheimers Dis. 2011; 2011:810981. PMC: 3199079. DOI: 10.4061/2011/810981. View

11.

Youmans K, Tai L, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M . APOE4-specific changes in Aβ accumulation in a new transgenic mouse model of Alzheimer disease. J Biol Chem. 2012; 287(50):41774-86. PMC: 3516726. DOI: 10.1074/jbc.M112.407957. View

12.

Thomas R, Morris A, Tai L . Epidermal growth factor prevents -induced cognitive and cerebrovascular deficits in female mice. Heliyon. 2017; 3(6):e00319. PMC: 5463012. DOI: 10.1016/j.heliyon.2017.e00319. View

13.

Taxier L, Philippi S, Fleischer A, York J, LaDu M, Frick K . APOE4 homozygote females are resistant to the beneficial effects of 17β-estradiol on memory and CA1 dendritic spine density in the EFAD mouse model of Alzheimer's disease. Neurobiol Aging. 2022; 118:13-24. PMC: 10756028. DOI: 10.1016/j.neurobiolaging.2022.06.005. View

14.

Taxier L, Philippi S, York J, LaDu M, Frick K . APOE4 genotype or ovarian hormone loss influence open field exploration in an EFAD mouse model of Alzheimer's disease. Horm Behav. 2022; 140:105124. PMC: 8976745. DOI: 10.1016/j.yhbeh.2022.105124. View

15.

Lewandowski C, Maldonado Weng J, LaDu M . Alzheimer's disease pathology in APOE transgenic mouse models: The Who, What, When, Where, Why, and How. Neurobiol Dis. 2020; 139:104811. PMC: 7150653. DOI: 10.1016/j.nbd.2020.104811. View

16.

Stephen T, Cacciottolo M, Balu D, Morgan T, LaDu M, Finch C . APOE genotype and sex affect microglial interactions with plaques in Alzheimer's disease mice. Acta Neuropathol Commun. 2019; 7(1):82. PMC: 6528326. DOI: 10.1186/s40478-019-0729-z. View

17.

Jasienska G, Ellison P, Galbarczyk A, Jasienski M, Kalemba-Drozdz M, Kapiszewska M . Apolipoprotein E (ApoE) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy?. Proc Biol Sci. 2015; 282(1803):20142395. PMC: 4345437. DOI: 10.1098/rspb.2014.2395. View

18.

Barreto Oria R, de Almeida J, Moreira C, Guerrant R, Figueiredo J . Apolipoprotein E Effects on Mammalian Ovarian Steroidogenesis and Human Fertility. Trends Endocrinol Metab. 2020; 31(11):872-883. DOI: 10.1016/j.tem.2020.06.003. View

19.

Gerdes L, Gerdes C, Hansen P, Klausen I, Faergeman O . Are men carrying the apolipoprotein epsilon 4- or epsilon 2 allele less fertile than epsilon 3 epsilon 3 genotypes?. Hum Genet. 1996; 98(2):239-42. DOI: 10.1007/s004390050200. View

20.

Corbo R, Scacchi R, Cresta M . Differential reproductive efficiency associated with common apolipoprotein e alleles in postreproductive-aged subjects. Fertil Steril. 2004; 81(1):104-7. DOI: 10.1016/j.fertnstert.2003.05.029. View